Compounds of the formula ##STR2## or pharmaceutically acceptable salts thereof, wherein R is hydroxy, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, carboxyalkyl, carboxyalkenyl, hydroxyalkyl, hydroxyalkenyl, alkoxyalkyl, alkoxyalkenyl, haloalkyl, haloalkenyl, aryl, arylalkyl or (R.sub.1 R.sub.2 N)-alkyl, where R.sub.1 and R.sub.2 are each independently hydrogen alkyl or arylalkyl or taken together with the nitrogen to which they are attached form a 5- or 6-membered nitrogen-containing heterocycle are useful in the preparation of pharmaceutically important agents.
For example, U.S. Pat. No. 4,705,849, incorporated herein by reference, discloses boronic acid adducts of technetium-99m dioxime complexes having the formula EQU .sup.99m Tc X(Y).sub.3 Z II
wherein
X is an anion;
Y is a vicinal dioxime having the formula ##STR3## wherein R' and R" are each independently hydrogen, halogen, alkyl, aryl, amino or a 5- or 6-membered nitrogen- or oxygen-containing heterocycle, or together R' and R" are --(CR.sub.4 R.sub.5).sub.n wherein n is 3, 4, 5, or 6 and R.sub.4 and R.sub.5 are each independently hydrogen or alkyl;
and Z is a boron derivative of the formula EQU B--R. (ii)
These complexes are useful as imaging agents.
To prepare complexes of formula II, pertechnetate ion (in the form of a salt) is combined with a source of anion, a compound such as that of formula I and a dioxime of formula (i).
The pertechnetate ion can be obtained from commercially available technetium-99m parent-daughter generators; such technetium is in the +7 oxidation state. The generation of the pertechnetate ion using this type of generator is well known in the art and is described in more detail in U.S. Pat. No. 3,369,121 and 3,920,995. These generators are usually eluted with saline solution and the pertechnetate ion is obtained as the sodium salt.
The source of the anion moiety (X) can be water or it can be an acid or salt which dissociates to release an appropriate anion. Exemplary anionic moieties are hydroxyl, halide, isothiocyanato (N.dbd.C.dbd.S.sup..crclbar.) and thiocyanato (S--C.dbd.N.sup..crclbar.). The preferred anionic moieties are the halides, and chloride is the most preferred halide.
Brown et al., J. Organometallics, 5, 2300 (1986) describe a process for the preparation of methyl boronic acid which starts by reacting a compound of the formula EQU CH.sub.3 Li (iii)
with a compound of the formula ##STR4## in ether to provide the complex EQU [CH.sub.3 [(CH.sub.3).sub.2 CHO].sub.3 B.sup.-,Li.sup.+ ]. (v)
Treatment of complex (v) with an equivalent of hydrogen chloride provides ##STR5## The byproduct LiCl is removed by a tedious decantation. Hydrolysis of (vi) is then accomplished by the addition of water to give methyl boronic acid and the byproduct (CH.sub.3).sub.2 CHOH. The reaction solvent is then removed by distillation followed by a tedious azeotropic distillation with acetone of the excess water and apparently also the (CH.sub.3).sub.2 CHOH. The desired methyl boronic acid then remains as a residue. Thus, any byproduct LiCl not removed in the decantation process and any (CH.sub.3).sub.2 CHOH remaining from the distillation are present as impurities in the isolated methyl boronic acid. For the preparation of methyl boronic acid and similar compounds, i.e., compounds of formula I, especially on a manufacturing scale, an improved process would be a very useful addition to the art.